ABSTRACT: The various rare forms of hereditary peripheral neuropathies are known as Charcot-Marie-Tooth (CMT) disease and comprise a clinically and genetically heterogeneous set of neurological disorders. Traditionally, the disease is divided into demyelinating CMT1 forms with decreased nerve conduction velocities (NCV) and axonal CMT2 types with normal NCVs. More than 35 different genes have been identified for CMT and include autosomal dominant, recessive and X-linked forms. Still, only 40% of axonal (CMT2) cases currently have a mutation in one of the known genes. Importantly, the degree of phenotypic variation of severity, age-at-onset, and other measures within families is quite remarkable, yet genetic modifying factors have not been identified. Modifying factors in CMT families are likely targets for intervention and may well be important for other non-hereditary peripheral neuropathies, such as diabetic neuropathy. These studies have proven difficult however, primarily due to a lack of collections of patients with consistent clinical evaluations and their DNA. The proposed Rare Diseases Clinical Research Consortia (RDCRC) will substantially enhance our resources and quickly provide a large number of CMT patients and families evaluated with the same clinical severity score. A new generation of genetic tools is now available to tackle these important questions, such as genome-wide association studies and next-generation sequencing technology. These will also be applied to identify additional CMT2 genes in small pedigrees using innovative approaches.